Salt-sensitive hypertension is one of the prevalent forms of high blood pressure in the United States. The pathology of salt-sensitive hypertension is due primarily to an inability of the kidney to excrete salt. A balance exists between factors promoting renal salt and water retention and those favoring excretion. This project focuses on one factor favoring salt and water retention, superoxide (02-). Recent evidence shows that salt-sensitive hypertension may be a result of enhanced 02- production by the kidney. The thick ascending limb of the loop of Henle has been reported to be responsible for augmented salt retention in the Dahl salt-sensitive rat, but the effects of 02- on thick ascending limb transport are unknown. 02- has been shown to affect transport directly in non-renal tissue and to increase vascular reactivity and tubuloglomerular feedback by scavenging NO. However, there have been very few studies directly addressing the mechanism by which 02- alters urinary volume or sodium excretion, and essentially no studies addressing how reactive oxygen species may enhance net NaCl absorption by the various nephron segments. We hypothesize that salt-sensitive hypertension is at least in part due to elevated 02- levels in the thick ascending limb which cause inappropriate salt and water retention. 02- stimulates transport in this segment by generating isoprostanes that activate protein kinase C and by blunting the inhibitory effect of nitric oxide (NO). In Aim I we will study the effects of endogenously produced 02- on net NaC1 absorption by thick ascending limbs and identify the transporter(s) affected. In Aim II we will study the second messenger cascade activated by 02-. In Aim III we will study the interaction between NO and 02-in determining salt absorption by the thick ascending limb. In Aim IV we will study the effects of a high-salt diet on 02- production, and whether the salt content of the diet alters the ability of 02- to change renal function. In Aim V we will study the contribution of 02- to salt-sensitive hypertension in the Dahl rat and clarify how changes in 02- production or catabolism alter urinary volume and sodium excretion. This project will provide important new information concerning the regulation of salt absorption by 02- and its role in salt-sensitive hypertension.